Inhibition of In Vitro Contractions of Human Myometrium by Mibefradil, a T-Type Calcium Channel Blocker: Support for a Model Using Excitation-Contraction Coupling, and Autocrine and Paracrine Signaling Mechanisms

Abstract

Mibefradil inhibition of the bioelectrical signal and uterine contractile forces suggest that T-type calcium channels are important in the initiation of each contraction. Some results using indomethacin suggest that for a specific tissue or under some conditions, autocrine stimulation by prostaglandins may be important for recruitment of myocytes in the electrical phase. Stimulation by prostaglandins is likely important in the paracrine phase. Enhanced inhibition by nifedipine in the paracrine phase suggests the mechanism of action of nifedipine tocolytic effect is block of prostaglandin F2alpha (PGF2alpha) paracrine stimulation. Our initial model proposed at least two mechanisms (electrical and nonelectrical) for the recruitment of myocytes. Our modified model suggests that the electrical phase contains a prostaglandin autocrine mechanism in addition to excitation-contraction coupling, and the mechanism in the nonelectrical phase is prostaglandin paracrine signaling.

TRPC1, STIM1, and ORAI Influence Signal-Regulated Intracellular and Endoplasmic Reticulum Calcium Dynamics in Human Myometrial Cells1

“…T-type Ca 2þ channels have been implicated in the initiation of action potentials and in spontaneous contractile activity in myometrium [26,40]. With time in culture, myometrial cells such as those used in this study tend to lose robust responses to iso-osmotic KCldependent depolarization, indicative of dampened voltagedependent responses.…”

“…L-type Ca 2þ channel blockers inhibit Ca 2þ entry following myometrial cell membrane depolarization and have marked inhibitory effects on spontaneous and agonist-induced uterine contractile activity [1,26,[38][39][40]. T-type Ca 2þ channels have been implicated in the initiation of action potentials and in spontaneous contractile activity in myometrium [26,40].…”

“…In contrast, OT-induced SRCE and ER refilling were not inhibited by 10 À7 M nifedipine, a concentration of the L-type channel blocker that effectively inhibits OAG- [16], or by 10 À6 M mibefradil, a T-type calcium channel blocker that inhibits T-type electrical activity and contractions in human myometrium (Fig. 4A) [26]. CPA-induced SRCE was significantly inhibited, and ER store refilling was slowed by 10 À4 M gadolinium (Fig.…”

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

“…L-type channel blockers reduced both spontaneous and stimulus-induced myometrial contractions [39,40]. Nifedipine (5 nM) inhibited the amplitude of oxytocin-stimulated contractions with less effect on frequency [41] and at μM concentrations completely eliminated contractile activity [42]. The effect of nifedipine on human myometrial strips was more marked in term not-in-labor than in term-labor specimens [43].…”

“…The relatively specific T-type channel inhibitor mibefadril exhibited effects different from those of nifedipine on human myometrial contractile activity [41] and on spontaneous and OTstimulated mid-pregnant goat myometrial contractions [56]. In contrast, mibefradil affected rat myometrial cell contractile responses in a complex manner, suggesting effects on both Ca 2+ entry and intracellular release [57].…”